The invention relates to a process for the reparation of (1S,2R)-1-amino-2-indanol-(R,R)-tartrate methanol solvate, in which in a solvent a mixture of enantiomers of cis-1-amino-2-indanol reacts at an elevated temperature with (R,R)-tartaric acid and methanol and in which optically enriched (1S,2R)-1-amino-2-indanol-(R,R)-tartrate methanol solvate crystallizes out, after which the crystals are recovered.
Such a process is known from U.S. Pat. No. 5,420,353, in which in a highly diluted solution and in a water-free environment ( less than 0.1 H2O), (1S,2R)-1-amino-2-indanol-(R,R)-tartrate methanol solvate crystals are obtained after cooling to 20xc2x0 C.
It is a drawback of the known process, however, that it has to be carried out with a high degree of dilution.
The invention aims to provide a process whereby at a much higher concentration than in the known process (1S,2R)-1-amino-2-indanol-(R,R)-tartrate methanol solvate can be obtained in solid form.
This is achieved according to the invention in that the recovery takes place at a temperature between 10 and 50xc2x0 C. in the presence of 0-20 wt. % water relative to the amount of methanol plus solvent, on the understanding that if the reaction mixture is essentially free from water the recovery substantially takes place at a temperature between 30 and 50xc2x0 C.
The fact is that the applicant has found that if in the known process a high concentration of cis-1-amino-2-indanol is used it often happens that the undesired enantiomer of cis-1-amino-2-indanol, (1R,2S)-1-amino-2indanol, crystallizes out as diastereomeric tartrate, which is highly undesirable because of the unpredictability of this happening. In addition, the applicant surprisingly has found that when the recovery took place at an elevated temperature this undesired effect did not occur any more, and that this undesired effect did not occur either when the recovery was yet carried out at the same low temperature, but in the presence of a certain amount of water. Further it was found that the process according to the invention enabled a higher yield to be obtained and that the crystals could be obtained with a higher enantiomeric excess (e.e.) of (1S,2R)-1-amino-2-indanol, present in the salt, relative to the (1R,2S) enantiomer, compared with the results of the known process.
A process for the preparation of (1S,2R)-1-amino-2-indanol-(R,R)-tartrate methanol solvate, in which in a solvent a mixture of enantiomers of cis-1-amino-2-indanol reacts at an elevated temperature with (R,R)-tartaric acid and methanol and in which optically enriched (1S,2R)-1-amino-2-indanol-(R,R)-tartrate methanol solvate crystallizes out, after which the crystals are recovered, wherein the recovery takes place at a temperature between 10 and 50xc2x0 C. in the presence of 0-20wt. % water relative to the amount of methanol plus solvent, on the understanding that if the reaction mixture is essentially free from water the recovery substantially takes place at a temperature between 30 and 50xc2x0 C.
Preferably solutions of the reactants are first at least partially heated, then contacted with each other at an elevated temperature and next, after the reaction, the reaction mixture is cooled down. This offers the important advantage that with this process according to the invention significantly larger (1S,2R)-1-amino-2-indanol-(R,R)-tartrate methanol solvate crystals can be obtained than with the known process, which makes it easier to recover the crystals. The invention also relates to (1S,2R)-1-amino-2-indanol-(R,R)-tartrate methanol solvate crystals having such a particle size and particle size distribution that the D[v,0,9]xe2x80x94defined as the diameter in comparison with which 90% of the particles are smaller and 10% are largerxe2x80x94is larger than 95 xcexcm, in particular larger than 110 xcexcm, more in particular larger than 120 xcexcm. The particle size is determined using a Malvern 2600 apparatus; the quantities applied are explained in further detail in the manual going with the apparatus.
The process according to the invention is preferably carried out at relatively high concentrations; in particular, the applied amount of (1S,2R)-1-amino-2-indanol is 0.02 to 0.1 gram per ml of solvent, preferably between 0.05 and 0.08 g/ml.
The reaction is carried out in the presence of methanol. Preferably therefore methanol is used at the only organic solvent. Optionally, however, other organic solvents can be used as co-solvents besides methanol.
A suitable co-solvent is in principle any solvent which is inert in the reaction mixture, in which cis-1-amino-2-indanol and tartaric acid dissolve to an important extent and in which the salt of (R,R)-tartaric acid and (1S,2R)-1-amino-2-indanol as methanol solvate is poorly soluble, for instance i-butanol, n-butanol, dimethylformamide (DMF) or acetonitrile.
In addition the reaction mixture can contain water as well. The amount of water in the reaction mixture is between 0 and 20 wt. % relative to the amount of methanol plus organic solvent present in the reaction mixture. If the reaction mixture is essentially free from water, for instance contains less than 5 wt. % of water relative to methanol, then recovery takes place at a temperature between 30 and 50xc2x0 C., in particular between 30 and 37xc2x0 C. Preferably the reaction mixture contains 2-15 wt. % of water relative to the amount of methanol. The larger the amount of water in the reaction mixture, the lower the temperature at which the recovery can take place. The recovery will in practice mostly take place at a temperature between 10 and 40xc2x0 C.
The reaction of the mixture of enantiomers of cis-1-amino-2-indanol takes place at an elevated temperature, preferably at a temperature between 30 and 150xc2x0 C., in particular between 55 and 80xc2x0 C.
The starting material used in the process according to the invention is a mixture of-enantiomers of cis-1-amino-2-indanol, in particular a racemic mixture of cis-1-amino-2-indanol. In the framework of the invention a racemic mixture is understood to be a mixture in which the two enantiomers are present in equal amounts or in which one of the enantiomers is present with a minor excess, for instance an e.e. of less than 10%, over the other enantiomer.
The tartaric acid is preferably applied in a molar excess of (R,R)-tartaric acid relative to the mixture of enantiomers of cis-1-amino-2-indanol present in the reaction mixture, for instance 1.05-2.05 equivalents. In addition, due to addition of a strong acid, for instance hydrochloric acid, the optimum amount of (R,R)-tartaric acid to be applied can be lowered to 1 equivalent relative to the amount of (1S,2R)-1-amino-2-indanol. The total amount of acid to be added is at least 1 equivalent, relative to the mixture of enantiomers of cis-1-amino-2-indanol. The enantiomeric excess of (R,R)-tartaric acid to be applied is preferably as large as possible, for instance greater than 95%, in particular greater than 99%.
In a preferred embodiment of the process, in which racemic cis-1-amino-2-indanol is split up, a certain portion, for instance 15-50%, of the total amount of racemic cis-1-amino-2-indanol (wet) and (R,R)-tartaric acid is started from; after addition of methanol the mixture is heated up, for instance to reflux temperature. In order to ensure thorough mixing of the reaction components, the reactor contents are stirred. Then the rest of the cis-1-amino-2-indanol is supplied in the form of a solution in methanol, followed by cooling of the mixture and recovery of the crystals.
The (1S,2R)-1-amino-2-indanol-(R,R)-tartrate methanol solvate thus obtained can subsequently be subjected to a desalting step, resulting in optically active (1S,2R)-1-amino-2-indanol. (1S,2R)-1-amino-2-indanol is an important intermediate in the preparation of pharmaceuticals, for instance AIDS inhibitors, in particular indinavir sulphate, such as for instance described in U.S. Pat. No. 5,420,353, or by Thompson et al. in J. Med. Chem., Vol. 35 (1992), 1685.